Hydroxamic acid derivatives of phenoxy-acetic acids and analogs useful as therapeutic agents for treating anthrax poisoning

ABSTRACT

Compounds having the formula 
     
       
         
         
             
             
         
       
     
     wherein the symbols have the meaning described in the specification are hydroxamic acid derivatives of phenoxy-acetic acids and analogs capable of inhibiting the lethal effects of infection by anthrax bacteria and are useful in the treatment of poisoning by anthrax.

CLAIM OF PRIORITY

The present application claims the priority of U.S. provisionalapplication Ser. No. 60/898,966 filed on Feb. 1, 2007.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant no.R44AI052587 awarded by the National Institutes of Health. The USgovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds useful for treatment ofpoisoning by bacillus anthracis (anthrax infection or poisoning). Moreparticularly, the invention is directed to compounds capable ofinhibiting the lethal effects of infection by anthrax bacteria and areuseful in the treatment of poisoning by anthrax. The compounds of theinvention are hydroxamic acid derivatives of phenoxy-acetic acid and itsthio, and related analogs.

2. Background Art

Anthrax is a disease caused by infection of mammals, including humans,by bacillus anthracis. Spores of these bacteria can enter the mammalian,including human body, through skin abrasions, the digestive system orinhalation. Whereas anthrax poisoning in humans through skin abrasion orthe digestive system can often be treated with antibiotics, anthraxpoisoning in humans by ingestion of aerosol usually results in death ofthe infected individual.

Relatively recently, devices have been made which incorporate bacillusanthracis or its spores and are capable of releasing the bacteria or itsspores in aerosol form. This “weaponized” form of anthrax can serve as a“weapon of mass destruction” in biological warfare and is feared in theWestern World for its potential use by terrorists against civilianpopulations.

For all these reasons a serious effort has been made in the fields ofmedical and related biological research to elucidate the mode and agentof poisoning by bacillus anthracis and efforts have been made tosynthesize compounds which act as inhibitors of the lethal toxins andtherefore can treat the infection.

The following scientific publications describe or relate to the mannerof infection by the bacteria and to elucidation of the toxic factors andtheir mode of action in the mammalian, including human body: Dixon etal. (1999) N. England J. Med. 341. 815-26; Mock et al. Annu. Rev.Microbiol. 55. 647-71; Vitalae et al. (1998) Biochem. Biopphys. Res.Commun. 248, 706-11; Vitalae et al. (2000) Biochem J. 352 Pt 3, 739-45;Duesbery et al. (1998) Science 280. 734-7; Duesbery et al. InternationalPublication No. WO 99/50439; Hammond et al. (1998) Infect. Immun. 66,2374-8. A summary of these findings is that the toxin, called “lethalfactor”, released by bacillus anthraci is an enzyme that splits anessential peptide needed by mammalian organisms for signal transmission.Thus, inhibitors of this bacterial enzyme are candidates for drugs fortreatment of anthrax poisoning.

Published US Patent Application No. 2005/0148629 (Jul. 7, 2005)describes hydroxamic acid compounds which have the general formula shownbelow

where the R¹ is aryl, or heteroaryl, or heterocyclic and where Rrepresents a large number of potential substituents, including alkyl,and which can be used in the treatment of anthrax poisoning.

Published International Application WO 2005/027856 (Mar. 31, 2005)describe numerous compounds said to be inhibitors of anthrax lethalfactor.

Published International Application WO 97/24117 discloses compounds ofthe general formula

including some examples where the variable p=1, q=0 and m=1. Saidcompounds are said to be inhibitors of cyclic AMP phosphodiesterase.

Published European Patent Application EP 1 707 560 A1 includes formulas1 through 10 (pages 1-15) which purport to cover a very large number ofcompounds of diverging structures, some of which are pertinent to thecompounds of the present invention.

The present invention represents a further advance in the field byproviding hydroxamic acid derivatives of phenoxyacetic acid and analogswhich are useful to treat anthrax poisoning.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula 1

where

X is O, S, SO or SO₂;

R¹ is F, Cl, Br, I, alkyl of 1-3 carbons, alkoxy of 1-3 carbons,thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN, CF₃, OCF₃, OH, NH₂,NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, COOH or COO(C₁-C₆alkyl);

m is an integer having the value of 1 to 3;

R² is alkyl of 1-6 carbons; C₁-C₆ alkylphenyl where phenyl issubstituted with 0-3 R¹ groups, C₂-C₆alkenylO(CH₂)_(n)phenyl wherealkenyl has 2 to 6 carbons and one double bond and phenyl is substitutedwith 0-3 R¹ groups, C₁-C₆ alkylcyclohexyl, CH₂)_(n)OR³, (CH₂)_(n)NHR⁴,NR⁴C₁-C₆alkyl, (CH₂)_(n)CF₃, CH₂OCH₂phenyl; (CH₂)_(n)NH(CH₂)_(n)R⁴,(CH₂)_(n) NR⁶R⁴, (CH₂)_(n) NR⁶(CH₂)_(n)R⁴, (CH₂)_(n)O(CH₂)_(n)R⁴,(CH₂)_(n)OR⁴,

n is an integer having the value of 1 to 8;

R³ is H, alkyl of 1 to 6 carbons, alkylphenyl where the alkylgroup has 1to 6 carbons and the phenyl is substituted with 0-3 R¹ groups;

R⁴ is H, cyclohexyl, C(O)alkyl of 1 to 4 carbons, C(O)alkylphenyl wherethe alkylgroup has 1 to 4 carbons and the phenyl is substituted with 0-3R¹ groups or with a 5 to 6 membered heteroaryl group having 1 to 2heteroatoms selected from O, S, and N, or with a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S and N andcondensed with a phenylgroup, said heteroaryl or condensed heteroarylgroup itself substituted with 0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)COOH,(CH₂)_(p)phenyl where the phenyl is substituted with 0-3 R¹ groups orwith a NO₂ group, or R⁴ is C(O)OC₁-C₆alkyl, or R⁴ is CH(CH₃)phenyl wherethe phenyl is substituted with 0-3 R¹ groups, or R⁴ isC(O)(CH₂)_(p)phenyl where the phenyl is substituted with 0-3 R¹ groups,or R⁴ is C(O)CH(Ph)₂, C(O)—CH₂-(3PhO-)Ph, or R⁴ is a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S, and N, ora 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selectedfrom O, S and N and condensed with a phenylgroup, said heteroaryl orcondensed heteroaryl group itself substituted with 0-3 R¹ groups, or R⁴is CH₂heteroaryl where the heteroaryl group is 5 or 6 membered and has 1to 2 heteroatoms selected from O, S, or R⁴ is SO₂-alkyl of 1 to 6carbons, SO₂-Ph where the phenyl is substituted with 0-3 R¹ groups orwith NO₂ or with COOR⁵ group, or R⁴ is C(O)NH-alkylphenyl, orC(O)NH-phenyl where the alkyl group has 1 to 4 carbons and where thephenyl is substituted with 0-3 R¹ groups;

p is an integer having the value of 0 to 4;

R⁵ is alkyl of 1 to 6 carbons or phenyl substituted with 0-3 R¹ groupsor with an OPh group;

R⁶ is alkyl of 1 to 6 carbons;

the asterisk indicates an asymmetric carbon, the wavy line represents abond that can be in the R or in the S configuration,

or a pharmaceutically acceptable salt of said compound,

with the proviso that compounds selected from the group consisting ofcompounds identified below with structural formulas and designations ofthe variables R¹

where R¹ is H, 2-Me, 4-Me, 4-Br, 2-phenyl, 2-(3-propenyl), 4-O-n-Bu,2-Me-4-Br, 2,4-diCl, 2,4-diBr, 2,5-diCl, 2,4,5-triCl, 2,5-diCl-4-Me, or2,4-diCl-4-Br, and

where R¹ is 2-phenyl, 2-(3-propenyl), 2,3-dimethyl, or 2,4-diCl, and

where R¹ is H, 2-Me, 2—Cl, 2-OMe, 3-Me, 3—Cl, 3-OMe, 3-CF₃, 4-OMe,4-SMe, or 4-phenyl,and

are not included in the invention as novel composition of matter.

The present invention also relates to pharmaceutical compositionssuitable for administration to mammals, including humans, which includeone or more compounds of the invention and are used for treatment orprevention of anthrax poisoning.

Biological Activity, Modes of Administration Determining BiologicalActivity

As briefly noted above in the introductory section of this applicationfor patent, the most serious, often lethal results of anthrax poisoningare caused by a toxin that is released by bacillus anthracis within thehost. The toxin includes three proteins, one of which is azinc-dependent metalloprotease enzyme (lethal factor) that cleaves nearthe N termini of several MAP kinase kinase enzymes (MKKs) of the host.It is this disruption of key signaling pathways mediated by the host MKKenzymes that result in the severe and often lethal results of infectionby the bacteria.

An assay for identifying and measuring the effectiveness of potentialdrugs to treat anthrax poisoning is based on measuring the inhibitoryeffect of the candidate compound on the lethal factor enzyme. Theprocedure used in the present invention to measure the potentialefficiency of the compounds of the present invention is based, in asomewhat modified form, on the assay described by Cummings et al., Apeptide-based fluorescence resonance energy transfer assay for Bacillusanthracis lethal factor protease, PNAS, May 14, 2002, Vol 99, No. 106603-6606, expressly incorporated herein by reference. The gist of thisassay that a fluorogenic peptide substrate is incubated with the lethalfactor enzyme in the presence of the inhibitor and the inhibition of thelethal factor is measured by measuring the fluorescence intensity of thecleaved substrate. A description of the actual assay conditions used forevaluating the compounds of the present invention is provided below.

Assay Procedure

Inhibitors were solubilized in 100% DMSO at 10 mM, then diluted to thefinal desired concentration and 10% final DMSO in the assay. Lethalfactor protease (20 nM) and inhibitor were briefly incubated at roomtemperature in the assay buffer (20 mM Hepes, 0.05% Tween 20, 0.02%NaN₃, pH 7.4), and the reaction started by the addition of 12.5 μM finalof the fluorogenic peptide substrate, MAPKKide™ (List BiologicalLaboratories, Inc, Campbell, Calif.). The final volume was 50 μL, inhalf area black microtiter plates (Costar). Fluorescence intensity (Ex:320 nm, Em: 420 nm) was monitored for 15 minutes at room temperature(Gemini XS, Molecular Devices), and the K_(i) ^(app) values werecalculated using the program BatchKi (BioKin Ltd., Pullman, Wash.).Generally speaking a compound is considered active in this assay if thecalculated K_(i) ^(app) value is less than 300 (<300) μM.

Modes of Administration

The compounds of the invention are useful for treating anthraxpoisoning.

The compounds of this invention may be administered systemically throughoral, intravenous or other modes of systemic administration, dependingon such considerations as the severity of the anthrax infection treated,quantity of drug to be administered, and numerous other considerations.For oral administration the drug may be confected as a powder, pill,tablet or the like or as a syrup or elixir suitable for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate the compounds of the invention in suppository form or asextended release formulation for deposit under the skin or intramuscularinjection. For each type of administration appropriate pharmaceuticalexcipients are likely to be added to the drug. The nature of suchexcipients for each type of systemic administration is well known in theart and need not be described here further.

A useful therapeutic or prophylactic concentration will vary from withthe precise identity of the drug, with the severity of the anthraxinfection being treated and the patient's susceptibility to treatment.Accordingly, no single concentration will be uniformly useful, but willrequire modification depending on the particularities of each situation.However, it is anticipated that an amount between 0.1 and 10 mg per kgof body weight per day will effect a therapeutic result.

Results of the Assay Measuring Lethal Factor Inhibitory Activity

Specific examples of compounds within the scope of the present inventionare shown by their respective structural formulas in Tables 1 through 3,and their activity in the above-described assay is also indicated.

TABLE 1

LF (FRET) Compound # X R² K_(i) ^(app) μM) 167182 —O— —H 29.2 167163 —O—n-Bu 5.5 167303 —S— n-Bu 2.5 167316 —SO— n-Bu 18.0 167351 syn-SO— n-Bu10.3 167352 anti-SO— n-Bu 67 167304 —SO₂— n-Bu 30

TABLE 2

LF Com- (FRET) pound # R¹ R² K_(i) ^(app) μM) 168090 H (R) n-Pr 3.70168093 H (R) —(CH₂)₂—OH 23.1 168176 H (R) —(CH₂)₄—OH 1.78 168142 H (R)—(CH₂)₂—N(Me)—(CH₂)₃-(3-Me-4- 1.12 F—Ph) 168143 H

1.67 168097 H (R) —(CH₂)₄NH—CH₂-(3-Me-4-F—Ph) 0.21 168100 Me (R)—(CH₂)₄NH—CH₂-(3-Me-4-F—Ph) 0.58 168178 H (R) —(CH₂)₄NH—CH₂-3-(4-F—Ph)Ph0.13 168177 H (R) —(CH₂)₄NH—CH₂-2-thienyl 0.21 168184 H (R)—(CH₂)₄NH—CH₂-2-furanyl 0.75 168183 H (R) —(CH₂)₄NH—CH₂-2- 0.17bicyclo[2.2.1]heptan-2-yl 168185 H (R),(E) —CH₂—CH═CH—CH₂—OCH₂Ph 0.77168101 H (R) —(CH₂)₄—OCH₂Ph 1.48 168113 H (R) —(CH₂)₄—OCH₂-(3-Me-4-F—Ph)0.54 168135 Me (R) —(CH₂)₄—OCH₂-(3-Me-4-F—Ph) 3.03

TABLE 3

LF (FRET) Compound # Ar K_(i) ^(app) μM) 168128 4-F—Ph— 61.1 1681294-Cl—Ph— 83.9 168130 3,4-diF—Ph— 26.2 168127 3-Cl-4-F—Ph— 31.2 1681153,5-diMe-4-F—Ph— 2.52

TABLE 4

LF (FRET) Compound # R² K_(i) ^(app) μM) 168160 (E)—CH₂—CH═CH—CH₂—OCH₂Ph 1.25 168187 —(CH₂)₄—OCH₂Ph 1.07

GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl and branched-chain alkyl. Unless specified otherwise,lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and 3 to 6 carbonsfor lower branch chained alkyl groups. A pharmaceutically acceptablesalt may be prepared for any compound used in accordance with theinvention having a functionality capable of forming a salt, for examplean acid or an amino functionality. A pharmaceutically acceptable salt isany salt which retains the activity of the parent compound and does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids. Preferred salts are those formed with inorganic acids such ashydrochloric acid, sulfuric acid or phosphoric acid. Any of a number ofsimple organic acids such as mono-, di- or tri-acid may also be used.

Some compounds used in accordance with the present invention may havetrans and cis (E and Z) isomers. Unless specific orientation ofsubstituents relative to a double bond or a ring is indicated in thename of the respective compound, and/or by specifically showing in thestructural formula the orientation of the substituents relative to thedouble bond or ring the invention covers trans as well as cis isomers.

Some of the compounds used in accordance with the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all isomers per se, as well as mixturesof cis and trans isomers, mixtures of diastereomers, pure enantiomers(optical isomers) and 50:50 (racemic) or other ratio mixtures ofenantiomers as well. In some cases one compound of a diastereomericspecies, or one specific enantiomer of a chiral compound is more activethan the other diastereomer(s) or optical isomer, and when such a caseis established it is indicated in the respective designation of thecompound.

General Synthetic Methodology

The novel compounds used in accordance with the invention areencompassed by the general Formula 1 provided above.

A general route for the synthesis of the compounds of Formula 1 wherethe variable X is O is shown in the General Scheme 1, below.

Referring now to General Scheme 1 a derivative of an alpha-bromo aceticacid ester (such as for example 1-bromo hexanoic acid methyl ester) anda substituted phenol serve as starting materials. The variables R¹, mand R² are as defined in Formula 1. Such starting materials are eitheravailable commercially or can be obtained in accordance with knownchemical scientific and or patent literature or by such modifications ofknown synthetic procedures which will be readily apparent to thoseskilled in the art. The alpha-bromo acetic acid ester derivative and thesubstituted phenol are reacted in a suitable solvent, such asdimethylformamide (DMF) in the presence of an acid acceptor, such aspotassium carbonate to give the compound shown in the scheme asIntermediate Formula 1. Intermediate Formula 1 is reacted withhydroxylamine hydrochloride in the presence of potassium cyanide in asuitable solvent such as mixture of tetrahydrofuran (THF) and methanol(MeOH) to give the compounds of Formula 2. The compounds of Formula 2are in the scope of the present invention and represent a subgenus ofthe compounds of Formula 1.

A general route for the synthesis of the compounds of Formula 1 wherethe variable X is S is shown in the General Scheme 2, below. The stepsof this scheme are analogous to the steps of General Scheme 1 exceptthat one starting material is a substituted thiophenol instead of thesubstituted phenol of the first scheme. The resulting compounds ofFormula 3 are in the scope of the present invention and represent asubgenus of the compounds of Formula 1.

A general route for the synthesis of the compounds of Formula 1 wherethe variable X is SO₂ is shown in the General Scheme 3, below. Inaccordance with this scheme the Intermediate of Formula 2 is oxidizedwith a strong oxidizing agent, such as the commercially availableproprietary reagent known as Oxone® (potassium peroxymonosulfate) toprovide the sulfone shown as Intermediate Formula 3. Other suitableoxidizing agents for this latter reaction are hydrogen peroxide orm-chloroperbenzoic acid. Intermediate Formula 3 is then reacted withhydroxylamine hydrochloride in the presence of potassium cyanide in amixture of tetrahydrofuran (THF) and methanol (MeOH) to give thecompounds of Formula 4. The compounds of Formula 4 are in the scope ofthe present invention and represent a subgenus of the compounds ofFormula 1.

A general route for the synthesis of the compounds of Formula 1 wherethe variable X is SO is shown in the General Scheme 4, below. Inaccordance with this scheme the Intermediate of Formula 2 is oxidizedwith hydrogen peroxide (H₂O₂ 30% solution) in a solvent such asmethanol. The resulting sulfoxide isomers of syn and anti configuration(Intermediate of Formula 4) are reacted with hydroxylamine hydrochloridein the presence of potassium cyanide in a mixture of tetrahydrofuran(THF) and methanol (MeOH) to give the compounds of Formula 5 (syn andanti configuration). The compounds of Formula 5 are in the scope of thepresent invention and represent a subgenus of the compounds of Formula1.

General Scheme 5 discloses a synthetic route for the preparation ofcompounds of the invention where the variable X is O, and R² is(CH₂)_(n)NHR⁴ and R⁴ is (CH₂)_(p)phenyl with the phenyl substituted inthe manner described in connection with Formula 1. One starting materialin this scheme is bromo-acetic acid ethyl (methyl or other alkyl) esterand the other is a phenol substituted with 0 to 3 R¹ groups. Thevariable R¹ is defined as in connection with Formula 1. Generallyspeaking, in the description of these synthetic schemes, unlessotherwise indicated the variables are defined as in connection withFormula 1. The two starting materials are reacted in the presence ofstrong base, such as KOH to pride a phenoxyacetic acid derivative ofIntermediate Formula 6. Intermediate Formula 6 is then converted to thecorresponding acid chloride by treatment with phosgene (COCl₂) in asuitable solvent or solvent mixture, such as DMF and DCM. The acidchloride of Intermediate Formula 7 is then reacted with(S)-(4)-isopropyl-2-oxazolidinone (available from commercial sources,eg. Aldrich Chemical Co.) in the presence of butyl lithium (BuLi) in anaprotic solvent, such as THF to give Intermediate Formula 8. TheIntermediate Formula 8 is then reacted with an allylic halide forexample a benzyloxyallyl-iodide derivative, shown in the reaction schemein the presence of lithium bis(trimethylsilyl)amide (LiHMDS) to provideIntermediate Formula 9. The benzyl protective group of the IntermediateFormula 9 is removed and at the same time the carbon-carbon double bondis reduced by catalytic hydrogenation to give Intermediate Formula 10.The Intermediate Formula 10 is oxidized by treatment with1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martinperiodinane reagent) in dichloromethane to give the aldehyde compound ofIntermediate Formula 11. The Intermediate Formula 11 is then reactedwith a phenylalkylamine shown in the scheme to first provide a Schiffbase compound that is reduced by treatment with sodiumtriacetoxyborohydride (NaBH(OAc)₃) to give Intermediate Formula 12. TheIntermediate Formula 12 is then reacted with hydroxylamine hydrochloridein the presence of potassium cyanide in a mixture of tetrahydrofuran(THF) and methanol (MeOH) to give the compounds of Formula 6. Thecompounds of Formula 6 are in the scope of the present invention andrepresent a subgenus of the compounds of Formula 1.

General Scheme 6 discloses a synthetic route for the preparation ofcompounds of the invention where the variable X is O, and R² is(CH₂)₄OR⁴ and R⁴ is (CH₂)_(p)phenyl with the phenyl substituted in themanner described in connection with Formula 1. One starting material inthis scheme is 1,4-dihydroxy-2-butene, and the other is a1-bromo-omega-phenyl substituted with 0 to 3 R¹ groups. These startingmaterials are either available commercially or from the chemicalscientific and patent literature, or by such modification of the knownprocedures that will be readily apparent to those skilled in the art.The two starting materials are reacted in the presence of sodium hydridein an aprotic solvent, such as THF, to give Intermediate Formula 13. TheIntermediate Formula 13 is then reacted with tripehylphosphine andiodine to give the iodo compound of Intermediate Formula 14. TheIntermediate Formula 14 is reacted with a (S)-(3phenoxy)acetyl-4-isopropyloxazolidine-2-one (Intermediate Formula 8 inGeneral Scheme 5) to provide Intermediate Formula 15. The olefinic bondof the compound of Intermediate Formula 15 is removed by hydrogenationto give Intermediate Formula 16. The Intermediate Formula 16 isconverted by treatment with hydroxylamine hydrochloride in the presenceof potassium cyanide in a mixture of tetrahydrofuran (THF) and methanol(MeOH) to the compounds of Formula 7. The compounds of Formula 7 are inthe scope of the present invention and represent a subgenus of thecompounds of Formula 1.

General Scheme 7 discloses another synthetic route for the preparationof compounds of the invention where the variable X is O, and R² is(CH₂)_(n)NR⁶R⁴ and R⁴ is (CH₂)_(p)phenyl with the phenyl substituted inthe manner described in connection with Formula 1, and where thevariable p is greater than one (1). The scheme is actually shown formaking of compounds of the invention where p represents the integerthree (3) and R⁶ is methyl. However, a person of ordinary skill in theart of synthetic organic chemistry would be readily able to modify thedisclosure of General Scheme 7 to prepare compounds within the scope ofthis disclosure where R⁶ is other than methyl, and the variable p is aninteger other than three (3).

The staring material in this scheme is a 2-phenoxyacetyl chloride wherethe phenyl group is substituted with 0 to 3 R¹ groups. This startingmaterial is either available commercially or from the chemicalscientific and patent literature, or by such modification of the knownprocedures that will be readily apparent to those skilled in the art.The starting material is reacted with (S)-4-benzyl-2-oxazolidinone(available from commercial sources) in the presence of n-butyl lithiumin an aprotic solvent, such as THF, to give Intermediate Formula 17. TheIntermediate Formula 17 is reacted with allyl iodide of the formulashown in the reaction scheme in the presence of LiHMDS in an aproticsolvent, such as THF, to provide Intermediate Formula 18. The olefinicbond of the Intermediate Formula 18 is broken by oxidation with ozoneand the resulting intermediate ozonide is decomposed by the addition oftriphenylphosphine to give the aldehyde compound of Intermediate Formula19. The Intermediate Formula 19 is reacted with anN-methyl-N-alkylphenylamine such as 3-phenyl-N-methylpropan-1-aminewhere n=3 and the phenyl group is substituted with 0 to 3 R¹ groups togive an intermediate imine (not shown in the scheme) that is thenreduced with NaBH(OAc)₃ provide Intermediate Formula 20. An example fora reagent of the latter formula and one that is utilized for thepreparation of preferred compounds of the invention is4-fluoro-3-methylphenyl)-N-methylpropan-1-amine. A specific route forthe synthesis of 4-fluoro-3-methylphenyl)-N-methylpropan-1-amine isdisclosed below in Specific Scheme 7. Those having ordinary skill in theart can readily modify the disclosure of Specific Scheme 7 to obtainother N-methyl-N-alkylphenylamine compounds where n=0 to 6 and thephenyl group is substituted with 0 to 3 R¹ groups. Intermediate Formula20 is reacted with hydroxylamine hydrochloride in the presence ofpotassium cyanide in a mixture of tetrahydrofuran (THF) and methanol(MeOH) to the compounds of Formula 8. The compounds of Formula 8 are inthe scope of the present invention and represent a subgenus of thecompounds of Formula 1.

Preferred Examples

Referring now to the variable R¹ in Formula 1, in the compounds of theinvention R¹ represents a substituent on the phenyl group shown in theformula. In the preferred compounds of the invention R¹ is F, Cl,methyl, or methoxy. The variable m is preferably the integer selectedfrom 1, 2 and 3. Even more preferably the variable m is 2 or 3.Particularly preferred are compounds of the invention where m is 2, andthe R¹ are methyl and fluoro, with the methyl group being in the 3(meta) position and the fluoro being in the 4 (para) position relativeto the X group. Also particularly preferred are compounds where m is 3,and there is a methyl group in the 3,5 (meta, meta) positions and afluoro in the 4 (para) position of the phenyl ring.

In most of the preferred compounds of the invention the variable X is Oor S, with O being preferred over S.

Referring now to the variable R² in Formula 1 in the preferred compoundsof the invention R² is H, alkyl of 1 to 4 carbons, cyclohexyl,alkylphenyl where the alkyl group has 1 to 3 carbons, CH₂OCH₂-phenyl,(CH₂)_(n)CF₃ where n is 2 or 3, CH₂OR³ where R₃ is H or t-butyl.

Compounds of the invention are also preferred where the variable R² is(CH₂)_(n)NHR⁴, (CH₂)_(n)OR⁴ and (CH₂)_(n)NR⁶(CH₂)_(p)R⁴ where n is theinteger 3, 4 or p is 3, 5 and R⁴ is H, C(O)CH₃, C(O) substituted phenyl,CH₂-phenyl, CH₂-thienyl, CH₂furanyl, where the phenyl group issubstituted with the preferred examples of the R¹ group or with aphenoxy group, C(O)CH₂-phenyl, CH(phenyl)₂, C(O)(CH₂)₂COOH, dimethylsubstituted pyrrolyl, SO₂alkyl of 1 to 3 carbons, SO₂phenyl where thephenyl is substituted with the preferred examples of R¹ or with a nitro(NO₂) group. Still preferred are compounds where R⁴ isC(O)NH-alkylphenyl where the alkyl group has 1 to 4 carbons and thephenyl group is substituted with the preferred examples of the R¹ group.

The most preferred compounds of the invention are shown in Tables 1through 4 above and in the experimental description below.

Experimental

Reaction schemes and experimental description of the synthesis of thepresently most preferred compounds of the invention are provided below.The LC/MS data given was obtained using the following conditions:LC/MSD/ELSD analysis performed in ESI positive mode with an Agilent 1100LC/MSD VL system equipped with Agilent 1100 HP PDA and Sedex 75 ELSDdetectors. Column: Zorbax Eclipse SD-C18, 5 μm, 4.6×75 mm; Temperatureset at 25° C.; Mobile Phase: % A=0.025% trifluoroacetic acid-water, %B=0.025% trifluoroacetic acid-acetonitrile; or % A=0.10% formicacid-water, % B=0.10% formic acid-acetonitrile; Linear Gradient: 20%-98%B in 15 min.; Flow rate: 1.0 mL/min.; ELSD gain set@3; UV set at 254 nmand 214 nm.

Reagents and conditions: (a) 1 eq of 4-fluoro-3-methylphenol, 5 eq ofK₂CO₃, DMF, rt; (b) KCN (5 mol %), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

2-(4-Fluoro-3-methyl-phenoxy)-hexanoic acid methyl ester (IntermediateA)

To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404mmol) and 4-fluoro-3-methylphenol (0.303 g, 2.404 mmol) in 15 mL of DMF,was added K₂CO₃ (1.661 g, 12.020 mmol). After stirring at roomtemperature under N₂ for 88 h, the reaction mixture was diluted with 60mL of water and extracted with dichloromethane (60 mL×3). The organicextracts were combined and dried over anhydrous Na₂SO₄. After removingthe solvent under reduced pressure, the product was isolated by Flashchromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes togive the title compound as yellow oil (0.467 g, 76% yield). LC-MS:t_(R)=10.5 min; m/z 255 (M+H)⁺.

2-(4-Fluoro-3-methyl-phenoxy)-hexanoic acid hydroxyamide (Compound167163)

To a solution of 2-(4-fluoro-3-methyl-phenoxy)-hexanoic acid methylester (0.467 g, 1.838 mmol) in 5 mL of THF/MeOH/50% NH₂OH—H₂O (2:2:1),was added KCN (0.006 g, 0.092 mmol). After stirring at room temperaturefor 15 h, the reaction mixture was diluted with 60 mL of water andextracted with ethyl acetate (60 mL×3). The organic extracts werecombined and dried over anhydrous Na₂SO₄. After removing the solventunder reduced pressure, the product was isolated by Flash chromatography(silica gel) eluting with 0-10% methanol/dichloromethane to give thetitle compound a white solid (0.286 g, 61% yield). LC-MS: t_(R)=6.9 min,m/z 256 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.92 (t, J=6.90 Hz, 3H),1.32-1.50 (m, 4H), 1.86-1.93 (m, 2H), 2.21 (d, J=1.80 Hz, 3H), 4.50 (t,J=6.00 Hz, 1H), 6.72-6.77 (m, 1H), 6.80-6.83 (m, 1H), 6.91 (t, J=9.00Hz, 1H).

Reagents and conditions: (a) 1 eq of 4-fluoro-3-methyl-benzenethiol, 10eq of Et₃N, DCM, rt; (b) KCN (5 mol %), THF/MeOH/50% NH₂OH—H₂O (2:2:1),rt.

2-(4-Fluoro-3-methyl-phenylsulfanyl)-hexanoic acid methyl ester(Intermediate A2)

To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404mmol) and 4-fluoro-3-methyl-benzenethiol (0.340 g, 2.404 mmol) in 20 mLof dichloromethane, was added triethylamine (3.3 mL, 12.020 mmol). Afterstirring at room temperature under N₂ for 46 h, the reaction mixture wasdiluted with dichloromethane and washed with 1N HCl and brine. Theorganic layer dried over anhydrous Na₂SO₄. After removing the solventunder reduced pressure, the product was isolated by Flash chromatography(silica gel) eluting with 0-20% ethyl acetate/hexanes to give the titlecompound as colorless oil (0.596 g, 92% yield). LC-MS: t_(R)=11.2 min;m/z 271 (M+H)⁺.

2-(4-Fluoro-3-methyl-phenylsulfanyl)-hexanoic acid hydroxyamide(Compound 167303)

To a solution of 2-(4-fluoro-3-methyl-phenylsulfanyl)-hexanoic acidmethyl ester (0.100 g, 0.370 mmol) in 5 mL of THF/MeOH/50% NH₂OH—H₂O(2:2:1), was added KCN (0.002 g, 0.037 mmol). After stirring at roomtemperature for 64 h, the reaction mixture was diluted with 60 mL ofwater and extracted with ethyl acetate (60 mL×3). The organic extractswere combined and dried over anhydrous Na₂SO₄. After removing thesolvent under reduced pressure, the product was isolated by Flashchromatography (silica gel) eluting with 0-10% methanol/dichloromethaneto give the title compound an off-white solid (0.053 g, 53% yield).LC-MS: t_(R)=7.2 min, m/z 272 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.90 (t,J=6.30 Hz, 3H), 1.34-1.35 (m, 4H), 1.65-1.72 (m, 1H), 1.78-1.88 (m, 1H),2.24 (s, 3H), 3.38 (dd, J=8.70, 6.30 Hz, 1H), 6.99 (t, J=9.00 Hz, 1H),7.30-7.33 (m, 1H), 7.37 (d, J=6.90 Hz, 1H).

Reagents and conditions: (a) 3 eq of Oxone®, MeOH/H₂O (2:1); (b) KCN (5mol %), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

2-(4-Fluoro-3-methyl-benzenesulfonyl)-hexanoic acid methyl ester(Intermediate A3)

To a solution of 2-(4-fluoro-3-methyl-phenylsulfanyl)-hexanoic acidmethyl ester (0.160 g, 0.592 mmol) in 15 mL of MeOH/H₂O (2:1), was addedOxone® (1.500 g, 1.776 mmol) in portions. After stirring at roomtemperature for 5 h, the reaction mixture was diluted with 60 mL ofwater and extracted with dichloromethane (60 mL×3). The organic extractswere combined and dried over anhydrous Na₂SO₄. After removing thesolvent under reduced pressure, the product was isolated by Flashchromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes togive the title compound as colorless semi-solid (0.153 g, 86% yield).LC-MS: t_(R)=9.2 min; m/z 303 (M+H)⁺.

2-(4-Fluoro-3-methyl-benzenesulfonyl)-hexanoic acid hydroxyamide(Compound 167304)

To a solution of 2-(4-fluoro-3-methyl-benzenesulfonyl)-hexanoic acidmethyl ester (0.153 g, 0.506 mmol) in 5 mL of THF/MeOH/50% NH₂OH—H₂O(2:2:1), KCN (0.003 g, 0.051 mmol) was added. After stirring at roomtemperature for 17 h, the reaction mixture was diluted with 60 mL ofwater and extracted with ethyl acetate (60 mL×3). The organic extractswere combined and dried over anhydrous Na₂SO₄. After removing thesolvent under reduced pressure, the product was isolated by Flashchromatography (silica gel) eluting with 0-10% methanol/dichloromethaneto give the title compound an off-white solid (0.079 g, 52% yield).LC-MS: t_(R)=6.0 min, m/z 304 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.87 (t,J=6.60 Hz, 3H), 1.22-1.34 (m, 4H), 1.87-1.94 (m, 2H), 2.36 (d, J=1.80Hz, 3H), 3.72 (dd, J=8.70, 6.60 Hz, 1H), 7.28 (t, J=9.00 Hz, 1H),7.72-7.75 (m, 1H), 7.78 (d, J=7.20 Hz, 1H).

Reagents and conditions: (a) H₂O₂ (30% solution), MeOH; (b) KCN (5 mol%), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

syn-2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoic acid methyl ester(Intermediate B4) anti-2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoicacid methyl ester (Intermediate C4)

To a solution of 2-(4-fluoro-3-methyl-phenylsulfanyl)-hexanoic acidmethyl ester (Intermediate A4, 0.320 g, 1.185 mmol) in 10 mL of MeOH,was added H₂O₂ (30%, 2 mL). After stirring at room temperature for 114h, the reaction mixture was quenched with NaHSO₃ solution and extractedwith dichloromethane (60 mL×3). The organic extracts were combined anddried over anhydrous Na₂SO₄. After removing the solvent under reducedpressure, the products were isolated by Flash chromatography (silicagel) eluting with 0-20% ethyl acetate/hexanes to giveanti-2-(4-fluoro-3-methyl-benzenesulfinyl)-hexanoic acid methyl ester ascolorless oil (fraction 1, 0.145 g, 43% yield, LC-MS: t_(R)=8.4 min; m/z287 (M+H)⁺) and syn-2-(4-fluoro-3-methyl-benzenesulfinyl)-hexanoic acidmethyl ester as a colorless oil (fraction 2, 0.088 g, 26% yield, LC-MS:t_(R)=8.3 min; m/z 287 (M+H)⁺).

syn-2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoic acid hydroxyamide(Compound 167351)

To a solution of cis-2-(4-fluoro-3-methyl-benzenesulfinyl)-hexanoic acidmethyl ester (0.088 g, 0.308 mmol) in 5 mL of THF/MeOH/50% NH₂OH—H₂O(2:2:1), was added KCN (0.002 g, 0.031 mmol). After stirring at roomtemperature for 24 h, the reaction mixture was diluted with 60 mL ofwater and extracted with ethyl acetate (60 mL×3). The organic extractswere combined and dried over anhydrous Na₂SO₄. After removing thesolvent under reduced pressure, the product was isolated by Flshchromatography (silica gel) eluting with 0-10% methanol/dichloromethaneto give the title compound an off-white solid (0.048 g, 55% yield). Pureanalytic sample was obtained by RP-HPLC purification. LC-MS: t_(R)=4.7min, m/z 288 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.92 (t, J=6.59 Hz, 3H),1.24-1.48 (m, 4H), 2.03-2.05 (m, 2H), 2.34 (s, 3H), 3.22 (dd, J=9.67,5.27 Hz, 1H), 7.25 (t, J=8.93 Hz, 1H), 7.48-7.51 (m, 1H), 7.54 (d,J=7.03 Hz, 1H).

anti-2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoic acid hydroxyamide(Compound 167352)

To a solution of trans-2-(4-fluoro-3-methyl-benzenesulfinyl)-hexanoicacid methyl ester (0.145 g, 0.507 mmol) in 5 mL of THF/MeOH/50%NH₂OH—H₂O (2:2:1), was added KCN (0.003 g, 0.051 mmol). After stirringat room temperature for 24 h, the reaction mixture was diluted with 60mL of water and extracted with ethyl acetate (60 mL×3). The organicextracts were combined and dried over anhydrous Na₂SO₄. After removingthe solvent under reduced pressure, the product was isolated by Flashchromatography (silica gel) eluting with 0-10% methanol/dichloromethaneto give the title compound an off-white solid (0.120 g, 82% yield). Pureanalytic sample was obtained by RP-HPLC purification. LC-MS: t_(R)=5.3min, m/z 288 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.82 (t, J=6.30 Hz, 3H),1.10-1.44 (m, 5H), 1.72-1.94 (m, 1H), 2.36 (s, 3H), 3.35 (dd, J=7.91,3.00 Hz, 1H), 7.28 (t, J=8.93 Hz, 1H), 7.57-7.61 (m, 1H), 7.64 (d,J=6.74 Hz, 1H).

Reagents and conditions: a) NaI, K₂CO₃, Acetone, 63° C., 3 h; b) 5% KOH(aq), dioxane, 25° C., 30 min; c) (COCl)₂,DMF, DCM, 25° C., 3 h; d)(S)-( )-4-Isopropyl-2-oxazolidinone, n-BuLi, THF, −70° C. to RT, 3 h; e)(4-Iodo-but-2-enyloxymethyl)-benzene, LiHMDS, THF, −70° C. to RT, 3 h;f) 10% Pd/C, H₂, EtOH, 25° C., 3 h; g) Dess-Martin periodinane, DCM, 25°C., 3 h; h) 4-Fluoro-3-methyl-benzylamine, NaBH(OAc)₃, DCE, 25° C., 8 h;i) NH₂—OH, KCN, H₂O, MeOH, THF, 25° C., 3 days.

Ethyl 2-(4-fluoro-3-methylphenoxy)acetate (A5)

To a solution of Bromo-acetic acid ethyl ester (1.3 g, 7.1 mmol) and4-Fluoro-3-methyl-phenol (1.0 g, 7.1 mmol) in 10 mL acetone was addedK₂CO₃ (979 mg, 7.1 mmol) and NaI (7.1 mg, 0.047 mmol) at 25° C. Thereaction mixture was stirred for 3 h at 63° C. and the temperature wasslowly reduced to room temperature over a period of 30 min. Evaporationof solvent left the crude from which the product was isolated by Flashcolumn chromatography eluting with 0% to 10% ethyl acetate/hexane togive the title compound, 1.1 g, as a light yellow oil.

MS (EI) m/z 212 (M⁺), 84 (M−128) base peak.

2-(4-Fluoro-3-methylphenoxy)acetic acid (B5)

To the solution of ethyl 2-(4-fluoro-3-methylphenoxy)acetate (1.1 g, 5.1mmol) in 10 mL dioxane was added 10 mL aqueous 5% KOH at 25° C. Afterbeing stirred for 30 min at room temperature the reaction was quenchedby the addition of 12 mL of 1M aqueous HCl. The mixture was extractedethyl acetate (2×40 mL) and the combined organic layers were washed withbrine (2×30 mL). The solution was dried over Na₂SO₄ before beingconcentrated under reduced pressure. The crude product was used directlyin the next reaction without further purification.

MS (EI) m/z 184 (M⁺), 139 (M−45) base peak.

2-(4-Fluoro-3-methylphenoxy)acetyl chloride (C5)

To the crude solution of 2-(4-Fluoro-3-methylphenoxy)acetic acidisolated above in 30 mL DCM was added Oxalyl chloride (776 mg, 6.1 mmol)at 25° C. followed by three drops DMF. After being stirred for 3 h at25° C., the solvent was evaporated under reduced pressure and theproduct directly in the next reaction without further purification.

MS (EI) m/z 202 (M⁺), 139 (M−63) base peak.

(S)-3-(2-(4-Fluoro-3-methylphenoxy)acetyl)-4-isopropyloxazolidin-2-one(D5)

To the solution of (S)-( )-4-Isopropyl-2-oxazolidinone (992 mg, 5.6mmol) in anhydrous 30 mL THF at −70° C. was slowly added n-BuLi (3.5 mL,5.6 mmol, 1.6 M in hexane) over 15 minutes. The reaction mixture wasstirred for 30 min at −70° C. and to it was slowly added a solution of2-(4-fluoro-3-methylphenoxy)acetyl chloride crude solution in 4 mL THF.The resulting mixture was stirred at −70° C. for 2 h and the temperaturewas slowly raised over a period of 1 h. The mixture was poured into 30mL saturated NH₄Cl and extracted with ethyl acetate (3×40 mL). Thecombined organic layers were washed with brine (2×30 mL) and dried overNa₂SO₄. The solvent was removed under reduced pressure and the productisolated by Flash column chromatography eluting with 0% to 50% ethylacetate/hexane to give 2.2 g of the title compound as a light yellowoil.

MS (EI) m/z 295 (M⁺), 43 (M−252) base peak.

(S)-3-((R,Z)-6-(Benzyloxy)-2-(4-fluoro-3-methylphenoxy)hex-4-enoyl)-4-isopropyloxazolidin-2-one(E5)

To the solution of lithium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol,1M in THF) in anhydrous 20 mL THF at −70° C. was slowly added over 15minutes(S)-3-(2-(4-fluoro-3-methylphenoxy)acetyl)-4-isopropyloxazolidin-2-one(295 mg, 1.0 mmol) as a solution in 3.0 mL THF. The reaction mixture wasstirred for 30 min at −70° C. and then was slowly added a pre-cooledsolution of (4-Iodo-but-2-enyloxymethyl)-benzene (576 mg, 2.0 mmol) in 3mL of THF. The resulting mixture was stirred at −70° C. for 1 h and thetemperature was slowly raised over a period of 2 h. The mixture waspoured into 20 mL saturated NH₄Cl and extracted with ethyl acetate (3×30mL). The combined organic layers were washed with brine (2×20 mL) anddried over Na₂SO₄. The solvent was removed under reduced pressure andthe product isolated by Flash column chromatography eluting with 0% to50% ethyl acetate/hexane to give 294 mg of the title compound as a lightyellow oil.

LC/MS: t_(R)=11.3 min. MS (API-ES) m/z 278 (M+H⁺+Na⁺).

(S)-3-((R)-2-(4-Fluoro-3-methylphenoxy)-6-hydroxyhexanoyl)-4-isopropyloxazolidin-2-one(F5)

(S)-3-((R,Z)-6-(benzyloxy)-2-(4-fluoro-3-methylphenoxy)hex-4-enoyl)-4-isopropyloxazolidin-2-one(250 mg, 0.54 mmol) was dissolved into 5 mL EtOH and to it added 10%Pd/C (250 mg). The solution was saturated with H₂ (stream of H₂ bubbledthrough solution) and then stirred for 3 h at room temperature under anatmosphere of hydrogen balloon. The mixture was filtered through a bedof Celite and rinsed with ethyl acetate. The solvent was removed underreduced pressure and the crude product used directly in the next stepwithout further purification.

MS (EI) m/z 367 (M⁺), 73 (M−294) base peak.

(R)-5-(4-Fluoro-3-methylphenoxy)-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-6-oxohexanal(G5)

To the crude solution of(S)-3-((R)-2-(4-fluoro-3-methylphenoxy)-6-hydroxyhexanoyl)-4-isopropyloxazolidin-2-oneisolated above (167 mg, 0.45 mmol) in 30 mL DCM was added Dess-Martinperiodinane (385 mg, 0.91 mmol) at 25° C. After being stirred for 3 h at25° C., the mixture was filtered through a bed of Celite and rinsed withmore DCM. The solvent was removed under reduced pressure and the productisolated by Flash column chromatography eluting with 0% to 50% ethylacetate/hexane to give 131 mg of the title compound as a light yellowoil.

MS (EI) m/z 365 (M⁺), 73 (M−292) base peak.

(S)-3-((R)-6-(4-Fluoro-3-methylbenzylamino)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-one(H5)

To a solution of(R)-5-(4-fluoro-3-methylphenoxy)-6-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-6-oxohexanal(70 mg, 0.19 mmol) in 3 mL DCE was added 4-Fluoro-3-methyl-benzylamine(32 mg, 0.23 mmol) followed by NaBH(OAc)₃ (56 mg, 0.26 mmol) and AcOH(13.8 mg, 0.23 mmol) at room temperature. The mixture was stirred for 8h at the room temperature. The reaction was quenched by pouring into 20mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture wasextracted with more ethyl acetate (3×15 mL) and the combined organiclayers washed with brine (2×10 mL) and dried over Na₂SO₄. The solventwas removed under reduced pressure and the crude product used directlyin the next step without further purification.

LC/MS: t_(R)=6.6 min. MS (API-ES) m/z 489 (M+H⁺)

(R)-6-(4-Fluoro-3-methylbenzylamino)-2-(4-fluoro-3-methylphenoxy)-N-hydroxyhexanamide(Compound 168097)

To a crude solution of(S)-3-((R)-6-(4-fluoro-3-methylbenzylamino)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-oneisolated above and dissolved in 2 mL of THF, methanol, and 50 wt % NH₂OHin H₂O (2:2:1) was added KCN (4.0 mg, 0.06 mmol). The resulting mixturestirred for 3 days at room temperature. Evaporation of solvent left thecrude from which the product was isolated RP-HPLC eluting with 80% to 2%CH₃CN/H₂O with 0.025% TFA to give the title compound, 52 mg, ascolorless oil.

¹H NMR (CD₃OD): δ 7.35 (d, 1H, J=7.9), 7.30 (m, 1H), 7.12 (t, 1H,J=8.8), 6.94 (t, 1H, J=9.1), 6.82 (dd, 1H, J=2.6 and 5.9), 6.76 (dd, 1H,J=3.2 and 8.9), 4.53 (t, 1H, J=6.2), 4.13 (s, 2H), 3.03 (t, 2H, J=6.7),2.30 (s, 3H), 2.20 (s, 3H), 1.94 (m, 2H), 1.74 (m, 2H), 1.58 (m, 2H).

LC/MS: t_(R)=4.7 min. MS (API-ES) m/z 393 (M+H⁺)

Reagents and conditions: a)) NaH, THF, 25° C., 8 h; b) Ph₃P, Im, I₂,DCM, 0 to 25° C., 3 h; c)(S)-3-(2-(4-fluoro-3-methylphenoxy)acetyl)-4-isopropyloxazolidin-2-one,LiHMDS, THF, −70° C. to RT, 3 h; d) Wilkinson's catalyst, H₂, benzene,25° C., 12 h; e) NH₂—OH, KCN, H₂O, MeOH, THF, 25° C., 3 days.

4-(4-Fluoro-3-methylbenzyloxy)but-2-en-1-ol (A6)

To a suspension of NaH (1.0 g, 60% oil dispersion) in 80 mL THF wasslowly added but-2-ene-1,4-diol (2.0 g, 22 mmol) as a solution in 5 mLTHF at room temperature. To this mixture was added dropwise4-bromomethyl-1-fluoro-2-methyl-benzene (5.0 g, 24 mmol) and theresulting stirred for 8 h at room temperature. The reaction was quenchedby the slow addition of 50 mL of saturated NH₄Cl and the mixtureextracted with ethyl acetate (3×80 mL). The combined organic layers werewashed with brine (2×60 mL) and dried over sodium sulfate. The solventwas removed under reduced pressure and the product isolated by Flashcolumn chromatography eluting with 0% to 50% ethyl acetate/hexane togive 2.3 g of the title compound as a light yellow oil.

1-Fluoro-4-((4-iodobut-2-enyloxy)methyl)-2-methylbenzene (B6)

To a solution of triphenylphosphine (2.6 g, 9.9 mmol) in anhydrous 40 mLDCM was added imidazole (1.4 mg, 20.4 mmol) and iodine (2.5 mg, 9.9mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. andthen 4-(4-Fluoro-3-methylbenzyloxy)but-2-en-1-ol (1.3 g, 6.2 mmol) in 10mL DCM was added to the mixture. The resulting mixture was stirred at 0°C. for 2 h and the temperature was slowly raised to room temp over aperiod of 2 h. 20 mL of 10% sodium thiosulfate was added and extractedwith more DCM (3×30 mL). The combined DCM layer was washed with brine(2×30 mL) and dried over sodium sulfate. Evaporation of solvent left thecrude product as an oil from which the product was isolated by Flashcolumn chromatography eluting with 0% to 10% ethyl acetate/hexane togive the title compound, 1.5 g, as a light yellow oil.

MS (EI) m/z 59 (M−261) base peak.

(S)-3-((R)-6-(4-Fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hex-4-enoyl)-4-isopropyloxazolidin-2-one(C6)

To the solution of lithium bis(trimethylsilyl)amide (1.9 mL, 1.29 mmol,1M in THF) in anhydrous 30 mL THF at −70° C. was slowly added over 15minutes(S)-3-(2-(4-fluoro-3-methylphenoxy)acetyl)-4-isopropyloxazolidin-2-one(480 mg, 1.6 mmol) as a solution in 4.0 mL THF. The reaction mixture wasstirred for 30 min at −70° C. and then was slowly added a pre-cooledsolution of 1-Fluoro-4-((4-iodobut-2-enyloxy)methyl)-2-methylbenzene(1.0 g, 3.2 mmol) in 4 mL of THF. The resulting mixture was stirred at−70° C. for 1 h and the temperature was slowly raised over a period of 2h. The mixture was poured into 40 mL saturated NH₄Cl and extracted withethyl acetate (3×40 mL). The combined organic layers were washed withbrine (2×30 mL) and dried over Na₂SO₄. The solvent was removed underreduced pressure and the product isolated by Flash column chromatographyeluting with 0% to 50% ethyl acetate/hexane to give 430 mg of the titlecompound as a light yellow oil.

MS (EI) m/z 129 (M−358) base peak.

(S)-3-((R)-6-(4-Fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-one(D6)

(S)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hex-4-enoyl)-4-isopropyloxazolidin-2-one(430 mg, 0.88 mmol) was dissolved into 4 mL benzene and to it addedWilkinson catalysis (81.0 mg, 0.088 mmol). The solution was saturatedwith H₂ (stream of H₂ bubbled through solution) and then stirred for 8 hat room temperature under an atmosphere of hydrogen balloon. The solventwas removed under reduced pressure and the product isolated by flashcolumn chromatography eluting with 0% to 30% ethyl acetate/hexane togive 418 mg of the title compound as a colorless oil.

MS (EI) m/z 489 (M⁺), 123 (M−366) base peak.

(R)-6-(4-Fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)-N-hydroxyhexanamide(Compound 168113)

To a solution of(S)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-one(100 mg, 0.20 mmol) dissolved in 2 mL of THF, methanol, and 50 wt %NH₂OH in H₂O (2:2:1) was added KCN (4.0 mg, 0.06 mmol). The resultingmixture stirred for 3 days at room temperature. The reaction wasquenched by the addition of 1M aqueous HCl (10 mL) and the resultingmixture extracted with ethyl acetate (3×10 mL). The combined organiclayers were washed with brine (2×5 mL). The product was isolated byflash column chromatography eluting with 0% to 10% methanol/DCM to givethe title compound (54.2 mg) as colorless oil.

¹H NMR (CD₃OD): δ 7.19 (d, 1H, J=7.9), 7.13 (m, 1H), 6.93 (m, 2H) 6.79(dd, 1H, J=5.9 and 6.2), 6.74 (dd, 1H, J=3.5 and 8.9), 4.48 (t, 1H,J=6.2), 4.41 (s, 2H), 3.48 (t, 2H, J=5.9), 2.24 (s, 3H), 2.21 (s, 3H),1.90 (m, 2H), 1.62 (m, 4H).

LC/MS: t_(R)=8.9 min. MS (API-ES) m/z 394 (M+H⁺)

Reagents and conditions: a) THF, 25° C., 8 h; b) 10% Pd/C, H₂, MeOH, 25°C., 3 h; c) DIBAL-H, DCM, −70° C., 30 min; d) MeNH₂·HCl, NaBH(OAc)₃,DCE, 25° C., 8 h.

(E)-Methyl 3-(4-fluoro-3-methylphenyl)acrylate (A7)

To a suspension of (triphenyl-15-phosphanylidene)-acetic acid methylester (3.6 g, 10.8 mmol) in 50 mL anhydrous THF at 25° C. was added4-Fluoro-3-methyl-benzaldehyde (1.0 g, 7.2 mmol) in 10 mL THF. Thereaction mixture was stirred for 8 h at 25° C. The solvent was removedunder reduced pressure and the product isolated by flash columnchromatography eluting with 0% to 20% ethyl acetate/hexane to give 1.3 gof the title compound as a white solid.

MS (EI) m/z 194 (M⁺), 163 (M−31) base peak.

Methyl 3-(4-fluoro-3-methylphenyl)propanoate (B7)

(E)-Methyl 3-(4-fluoro-3-methylphenyl)acrylate (1.3 g, 6.7 mmol) wasdissolved into 58 mL MeOH and to it added 10% Pd/C (750 mg). Thesolution was saturated with H₂ and then stirred for 3 h at roomtemperature under an atmosphere of hydrogen balloon. The mixture wasfiltered through a bed of Celite and rinsed with ethyl acetate. Thesolvent was removed under reduced pressure and the crude product useddirectly in the next step without further purification.

MS (EI) m/z 196 (M⁺), 136 (M−60) base peak.

3-(4-Fluoro-3-methylphenyl)propanal (C7)

To the solution of methyl 3-(4-fluoro-3-methylphenyl)propanoate isolatedabove in anhydrous 50 mL DCM at −70° C. was slowly added DIBAL-H (21 mL,21 mmol, 1 M in cyclohexane). The reaction mixture was stirred for 30min at −70° C. The excess reagents were destroyed by dropwise additionof 40 mL 4% aqueous H₂SO₄. The mixture was and extracted with ethylacetate (3×30 mL) and the combined organic layers washed with brine(2×20 mL) and dried over sodium sulfate. The solvent was removed underreduced pressure and the product isolated by flash column chromatographyeluting with 0% to 50% ethyl acetate/hexane to give 1.1 g of the titlecompound as a colorless oil.

MS (EI) m/z 166 (M⁺), 123 (M−43) base peak.

3-(4-Fluoro-3-methylphenyl)-N-methylpropan-1-amine (D7)

To a solution of 3-(4-fluoro-3-methylphenyl)propanal (1.0 g, 6 mmol) in20 mL MeOH was added MeNH₂HCl (556 mg, 7.2 mmol) followed by NaBH₃CN(452 mg, 7.2 mmol) at room temperature. The mixture was stirred for 2 hat the room temperature. The reaction was quenched by pouring into 20 mL5% aqueous NaOH and diluted with ethyl acetate. The mixture wasextracted with more ethyl acetate (3×15 mL) and the combined organiclayers washed with brine (2×10 mL) and dried over Na₂SO₄. The mixturewas concentrated under reduced pressure and the product isolated byflash column chromatography eluting with 0% to 10% MeOH/DCM to provide461 mg of the title compound as an colorless oil.

MS (EI) m/z 181 (M⁺), 44 (M−137) base peak.

Reagents and conditions:a) (S)-4-Benzyl-2-oxazolidione, n-Buli, THF,−70° C. to RT, 3 h; b0 allyl iodide, LiHMDS, THF, −70° C. to RT, 3 h;c)O₃, Ph₃P, DCM, −70° C. to RT, 4 h; d) 3-(4- Flouoro-3-methylphenyl)-N-methylpropan-1- amine, NaBH(OAc)₃, DCE, 25° C., 8 h; e) NH₂-OH, KCN,H₂O, MeOH, THF, 25° C., 3 days.

(S)-4-Benzyl-3-(2-(4-fluoro-3-methylphenoxy)acetyl)oxazolidin-2-one (A8)

To the solution of (S)-4-Benzyl-2-oxazolidinone (857 mg, 4.8 mmol) inanhydrous 30 mL THF at −70° C. was slowly added n-BuLi (3.0 mL, 4.8mmol, 1.6 M in hexane) over 15 minutes. The reaction mixture was stirredfor 30 min at −70° C. and to it was slowly added a solution of2-(4-fluoro-3-methylphenoxy)acetyl chloride crude solution in 4 mL THF.The resulting mixture was stirred at −70° C. for 2 h and the temperaturewas slowly raised over a period of 1 h. The mixture was poured into 30mL saturated NH₄Cl and extracted with ethyl acetate (3×40 mL). Thecombined organic layers were washed with brine (2×30 mL) and dried overNa₂SO₄. The solvent was removed under reduced pressure and the productisolated by Flash column chromatography eluting with 0% to 50% ethylacetate/hexane to give 1.5 g of the title compound as a light yellowoil.

MS (EI) m/z 343 (M⁺), 117 (M−226) base peak.

(S)-4-benzyl-3-((R)-2-(4-fluoro-3-methylphenoxy)pent-4-enoyl)oxazolidin-2-one(B8)

To the solution of lithium bis(trimethylsilyl)amide (5.2 mL, 5.2 mmol,1M in THF) in anhydrous 30 mL THF at −70° C. was slowly added over 15minutes(S)-4-Benzyl-3-(2-(4-fluoro-3-methylphenoxy)acetyl)oxazolidin-2-one (1.5g, 4.3 mmol) as a solution in 8.0 mL THF. The reaction mixture wasstirred for 30 min at −70° C. and then was slowly added a pre-cooledsolution of allyl iodide (2.2 g, 13 mmol) in 8 mL of THF. The resultingmixture was stirred at −70° C. for 1 h and the temperature was slowlyraised over a period of 2 h. The mixture was poured into 60 mL saturatedNH₄Cl and extracted with ethyl acetate (3×40 mL). The combined organiclayers were washed with brine (2×30 mL) and dried over Na₂SO₄. Thesolvent was removed under reduced pressure and the product isolated byFlash column chromatography eluting with 0% to 50% ethyl acetate/hexaneto give 521 mg of the title compound as a light yellow oil.

MS (EI) m/z 383 (M⁺), 91 (M−292) base peak.

(R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-fluoro-3-methylphenoxy)-4-oxobutanal(C8)

A solution of(S)-4-benzyl-3-((R)-2-(4-fluoro-3-methylphenoxy)pent-4-enoyl)oxazolidin-2-one(300 mg, 0.78 mmol) in 20 mL DCM was cooled to −70° C. and O₃ bubbledthrough it until the solution showed a faint blue color. The solutionwas purged of any remaining O₃ tubing by sparging with N₂ for about 30minutes. Triphenyl-phosphine (820 mg, 3.1 mmol) was added at −70° C. andthe temperature was slowly raised to room temperature. The resultingmixture was stirred for 3 h. After concentrating under reduced pressure,the product was isolated by silica gel chromatography to afford thetitle compound 125 mg, as an colorless oil.

(S)-4-benzyl-3-((R)-2-(4-fluoro-3-methylphenoxy)-4-((3-(4-fluoro-3-methylphenyl)propyl)(methyl)amino)butanoyl)oxazolidin-2-one(D8)

To a solution of(R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-fluoro-3-methylphenoxy)-4-oxobutanal(35 mg, 0.091 mmol) in 3 mL DCE was added3-(4-Fluoro-3-methylphenyl)-N-methylpropan-1-amine (22 mg, 0.12 mmol)followed by NaBH(OAc)₃ (29.5 mg, 0.14 mmol) and AcOH (7.2 mg, 0.12 mmol)at room temperature. The mixture was stirred for 8 h at the roomtemperature. The reaction was quenched by pouring into 10 mL 5% aqueousNaOH and diluted with ethyl acetate. The mixture was extracted with moreethyl acetate (3×15 mL) and the combined organic layers washed withbrine (2×10 mL) and dried over Na₂SO₄. The solvent was removed underreduced pressure and the crude product used directly in the next stepwithout further purification.

LC/MS: t_(R)=6.2 min. MS (API-ES) m/z 425 (M+H⁺−125)

(R)-2-(4-fluoro-3-methylphenoxy)-4-((3-(4-fluoro-3-methylphenyl)propyl)(methyl)amino)-N-hydroxybutanamide(Compound 168142)

To a crude solution of(S)-4-benzyl-3-((R)-2-(4-fluoro-3-methylphenoxy)-4-((3-(4-fluoro-3-methylphenyl)propyl)(methyl)amino)butanoyl)oxazolidin-2-oneisolated above and dissolved in 2 mL of THF, methanol, and 50 wt % NH₂OHin H₂O (2:2:1) was added KCN (4.0 mg, 0.06 mmol). The resulting mixturestirred for 3 days at room temperature. Evaporation of solvent left thecrude from which the product was isolated RP-HPLC eluting with 80% to 2%CH₃CN/H₂O with 0.025% TFA to give the title compound, 3.1 mg, ascolorless oil.

¹H NMR (CD₃OD): δ 7.10 (d, 1H, J=6.74), 7.03 (m, 1H), 6.96 (d, 1H, J9.37), 6.91-6.70 (m, 3H), 4.71 (t, 1H, J=5.56), 3.30 (m, 4H), 2.86 (s,3H), 2.65 (t, 2H, J=5.86), 2.22 (br, 6H), 2.01 (m, 4H).

LC/MS: t_(R)=5.4 min. MS (API-ES) m/z 407 (M+H⁺)

Reagents and conditions: a) mCPBA, DCM, 25° C., 20 h; b) 5% KOH (aq),dioxane, 25° C., 30 min.

Formic Acid 4-fluoro-3,5-dimethyl-phenyl ester (A9)

To a solution of 4-fluoro-3,5-dimethyl-benzaldehyde (1.0 g, 6.4 mmol) in20 mL DCM was added mCPBA (1.2 g, 7.6 mmol) at 25° C. After beingstirred for 20 h at 25° C., the reaction was quenched by the addition of40 mL of 5% aqueous potassium carbonate. The mixture was extracted DCM(3×30 mL) and the combined DCM layer was washed with brine (2×30 mL).The solution was dried over Na₂SO₄ before being concentrated underreduced pressure. The crude product was used directly in the nextreaction without further purification.

MS (EI) m/z 168 (M⁺), 125 (M−43) base peak.

4-Fluoro-3,5-dimethyl-phenol (B9)

To a solution of acetic acid 4-fluoro-3,5-dimethyl-phenyl ester in 10 mLdioxane was added 10 mL aqueous 5% KOH at 25° C. After being stirred for30 min at 25° C., the reaction was quenched by the addition of 12 mL of1M aqueous HCl. The mixture was extracted ethyl acetate (3×30 mL) andthe combined organic layers were washed with brine (2×30 mL). Thesolution was dried over Na₂SO₄ before being concentrated under reducedpressure. The product was isolated by silica gel chromatography toafford the title compound 987 mg, as a light yellow oil.

MS (EI) m/z 140 (M⁺), 140 (M) base peak.

Abbreviations:

DMF=dimethylformamide

HOBt=1-hydroxybenzotriazole

NMM=N-methylmorpholine

EDC=N-(-dimethylaminopropyl)-N′-ethylcarbodiimide

DCM=dichloromethane

DCE=1,2-dichloroethane

TFA=trifluoroacetic acid

MS=molecular sieves

LiHMDS=lithium bis(trimethylsilyl)amide

DIBAL-H=diisobutylaluminum hydride

TABLE 1 Compounds

2-(4-Fluoro-3-methyl-phenoxy)-N-hydroxy-acetamide (Compound 167182)Prepared according to General Scheme 1. LC-MS: t_(R) = 4.4 min, m/z 200(M + H)⁺

2-(4-Fluoro-3-methyl-phenoxy)-hexanoic acid hydroxyamide (Compound167163) Prepared according to General Scheme 1. LC-MS: t_(R) = 6.9 min,m/z 256 (M + H)⁺

2-(4-Fluoro-3-methyl-phenylsulfanyl)-hexanoic acid hydroxyamide(Compound 167303) Prepared according to General Scheme 2. LC-MS: t_(R) =7.2 min, m/z 272 (M + H)⁺

2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoic acid hydroxyamide(Compound 167316) Prepared according to General Scheme 4. LC-MS: t_(R) =4.7 and 5.3 min, m/z 288 (M + H)⁺

syn-2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoic acid hydroxyamide(Compound 167351) Prepared according to General Scheme 4. LC-MS: t_(R) =4.7 min, m/z 288 (M + H)⁺

anti-2-(4-Fluoro-3-methyl-benzenesulfinyl)-hexanoic acid hydroxyamide(Compound 167352) Prepared according to General Scheme 4. LC-MS: t_(R) =5.3 min, m/z 288 (M + H)⁺

2-(4-Fluoro-3-methyl-benzenesulfonyl)-hexanoic acid hydroxyamide(Compound 167304) Prepared according to General Scheme 3. LC-MS: t_(R) =6.0 min, m/z 304 (M + H)⁺

TABLE 2 Compounds

(R)-2-(4-Fluoro-3-methyl-phenoxy)-pentanoic acid hydroxyamide (Compound168090) Prepared according to General Scheme 5. ¹H-NMR (CD₃OD):. δ 6.91(t, 1H, J = 9.0), 6.80 (dd, 1H, J = 2.7 and 6.3), 6.73 (m, 1H), 4.46 (t,1H, J = 5.6), 2.21 (d, 3H, J = 2.0), 1.85 (m, 2H), 1.51 (m, 2H), 0.96(t, 3H, J = 7.4). LC/MS: t_(R) = 6.3 min. MS (API-ES) m/z 242 (M + H⁺)

(R)-2-(4-fluoro-3-methylphenoxy)-N,4-dihydroxybutanamide (Compound168093) Prepared according to General Scheme 7. ¹H-NMR (CD₃OD):. δ 6.92(t, 1H, J = 9.1), 6.82 (m, 1H), 6.75 (m, 1H), 4.66 (t, 1H, J = 6.2),3.73 (t, 2H, J = 6.7), 2.22 (s, 3H), 2.07 (m, 2H). LC/MS: t_(R) = 3.6min. MS (API-ES) m/z 244 (M + H⁺)

(R)-2-(4-fluoro-3-methylphenoxy)-N,6-dihydroxyhexanamide (Compound168176) Prepared according to General Scheme 5 LC/MS: t_(R) = 4.6 min.MS (API-ES) m/z 272 (M + H⁺)

(R)-2-(4-fluoro-3-methylphenoxy)-4-((3-(4-fluoro-3-methylphenyl)propyl)(methyl)amino)-N-hydroxybutanamide (Compound 168142)Prepared according to General Scheme 5. ¹H-NMR (CD₃OD):. δ 7.10 (d, 1H,J = 6.74), 7.03 (m, 1H), 6.96 (d, 1H, J = 9.37), 6.91-6.70 (m, 3H), 4.71(t, 1H, J = 5.56), 3.30 (m, 4H), 2.86 (s, 3H), 2.65 (t, 2H, J = 5.86),2.22 (br, 6H), 2.01 (m, 4H). LC/MS: t_(R) = 5.4 min. MS (API-ES) m/z 407(M + H⁺)

(R)-2-(4-fluoro-3-methylphenoxy)-N-hydroxy-4-((S)-3-(piperidin-1-ylmethyl)piperidin-1-yl)butanamide (COMPOUND 168143) Prepared accordingto General Scheme 7. LC/MS: t_(R) = 1.2 min. MS (API-ES) m/z 408 (M +H⁺)

(R)-6-(4-fluoro-3-methylbenzylamino)-2-(4-fluoro-3-methylphenoxy)-N-hydroxyhexanamide (Compound 168097) Prepared according to General Scheme5. ¹H-NMR (CD₃OD):. δ 7.35 (d, 1H, J = 7.9), 7.30 (m, 1H), 7.12 (t, 1H,J = 8.8), 6.94 (t, 1H, J = 9.1), 6.82 (dd, 1H, J = 2.6 and 5.9), 6.76(dd, 1H, J = 3.2 and 8.9), 4.53 (t, 1H, J = 6.2), 4.13 (s, 2H), 3.03 (t,2H, J = 6.7), 2.30 (s, 3H), 2.20 (s, 3H), 1.94 (m, 2H), 1.74 (m, 2H),1.58 (m, 2H). LC LC/MS: t_(R) = 4.7 min. MS (API-ES) m/z 393 (M + H⁺)

(R)-2-(4-fluoro-3,5-dimethylphenoxy)-6-(4-fluoro-3-methylbenzylamino)-N-hydroxyhexanamide (COMPOUND 168100) Prepared according to GeneralScheme 5. ¹H-NMR (CD₃OD):. δ 7.34 (d, 1H, J = 5.5), 7.30 (m, 1H), 7.11(t, 1H, J = 9.1), 6.61 (d, 2H, J = 5.8), 4.50 (t, 1H, J = 5.7), 4.13 (s,2H), 3.02 (t, 2H, J = 8.0), 2.30 (s, 3H), 2.19 (d, 6H, J = 1.8), 1.94(q, 2H, J = 6.9 and 15.2), 1.74 (m, 2H), 1.58 (m, 2H). LC LC/MS: t_(R) =5.1 min. MS (API-ES) m/z 407 (M + H⁺)

(R)-2-(4-fluoro-3-methylphenoxy)-6-((4′-fluorobiphenyl-3-yl)methylamino)-N-hydroxyhexanamide (Compound 168178) Prepared according toGeneral Scheme 5 ¹H-NMR (CD₃OD): δ 7.73-7.64 (m, 4H), 7.54 (t, 1H, J =7.6), 7.45 (dd, 1H, J = 1.1 and 7.4), 7.19 (t, 2H, J = 8.8), 6.91 (t,1H, J = 9.1), 6.81 (dd, 1H, J = 3.1 and 5.7), 6.74 (dd, 1H, J = 4.1 and8.3), 4.53 (t, 1H, J = 6.0), 4.26 (s, 2H), 3.08 (t, 2H, J = 7.8), 2.21(s, 3H), 1.94 (m, 2H), 1.74 (m, 2H), 1.60 (m, 2H). LC/MS: t_(R) = 5.8min. MS (API-ES) m/z 454 (M + H⁺)

(R)-2-(4-fluoro-3-methylphenoxy)-N-hydroxy-6-(thiophen-2-ylmethylamino)hexanamide (Compound 168177) Prepared according to GeneralScheme 5 ¹H-NMR (CD₃OD):. δ 7.57 (dd, 1H, J = 1.2 and 5.2), 7.28 (d, 1H,J = 3.2), 7.12 (t, 1H, J = 4.3), 6.94 (t, 1H, J = 9.1), 6.82 (dd, 1H, J= 3.0 and 5.9), 6.75 (dd, 1H, J = 3.5 and 8.7), 4.53 (t, 1H, J = 5.8),4.43 (s, 2H), 3.04 (t, 2H, J = 8.0), 2.22 (s, 3H), 1.94 (m, 2H), 1.74(m, 2H), 1.59 (m, 2H). LC/MS: t_(R) = 4.0 min. MS (API-ES) m/z 367 (M +H⁺)

(R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)-N-hydroxyhexanamide (COMPOUND 168101) Prepared according to General Scheme6. ¹H-NMR (CD₃OD):. δ 7.31 (s, 5H), 6.92 (t, 1H, J = 9.1), 6.82 (m, 1H),6.75 (m, 1H), 4.47 (m, 3H), 3.49 (t, 2H, J = 5.9), 2.20 (s, 3H), 1.90(m, 2H), 1.63 (m, 4H). LC LC/MS: t_(R) = 8.2 min. MS (API-ES) m/z 362(M + H⁺)

(R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)-N-hydroxyhexanamide (COMPOUND 168113) Prepared according to General Scheme6. ¹H-NMR: (CD₃OD):. δ 7.19 (d, 1H, J = 7.9), 7.13 (m, 1H), 6.93 (m, 2H)6.79 (dd, 1H, J = 5.9 and 6.2), 6.74 (dd, 1H, J = 3.5 and 8.9), 4.48 (t,1H, J = 6.2), 4.41 (s, 2H), 3.48 (t, 2H, J = 5.9), 2.24 (s, 3H), 2.21(s, 3H), 1.90 (m, 2H), 1.62 (m, 4H). LC LC/MS: t_(R) = 8.8 min. MS(API-ES) m/z 394 (M + H⁺)

(R)-2-(4-fluoro-3,5-dimethylphenoxy)-6-(4-fluoro-3-methylbenzyloxy)-N-hydroxyhexanamide (Compound 167135) Prepared according to General Scheme6. ¹H-NMR (CD₃OD):. δ 7.65 (m, 1H), 7.18 (d, 1H, J = 1.2), 6.95 (t, 1H,J = 8.8), 6.61 (d, 2H, J = 5.8), 4.45 (t, 1H, J = 6.2), 4.40 (s, 2H),3.47 (t, 2H, J = 6.1), 2.24 (s, 3H), 2.18 (d, 6H, J = 1.9), 1.89 (m,2H), 1.62 (m, 4H). LC/MS: t_(R) = 9.4 min. MS (API-ES) m/z 408 (M + H⁺)

TABLE 3 Compounds

2-(4-fluorophenoxy)-N-hydroxyacetamide (Compound 168128) Preparedaccording to General Scheme 1. ¹H-NMR (CD₃OD):. δ 7.00 (m, 4H), 4.52 (s,2H). LC/MS: t_(R) = 3.2 min. MS (API-ES) m/z 186 (M + H⁺)

2-(4-chlorophenoxy)-N-hydroxyacetamide (Compound 168129) Preparedaccording to General Scheme 1. ¹H-NMR (CD₃OD):. δ 7.27 (d, 2H, J = 9.0),6.97 (d, 2H, J = 9.0), 4.54 (s, 2H). LC/MS: t_(R) = 4.5 min. MS (API-ES)m/z 202 (M + H⁺)

2-(3,4-difluorophenoxy)-N-hydroxyacetamide (Compound 168130) Preparedaccording to General Scheme 1. ¹H-NMR (CD₃OD):. δ 7.19 (q, 1H, J = 9.3and 19.4), 6.96 (m, 1H), 6.79 (m, 1H), 4.53 (s, 2H). LC/MS: t_(R) = 4.0min. MS (API-ES) m/z 204 (M + H⁺)

2-(3-chloro-4-fluorophenoxy)-N-hydroxyacetamide (Compound 167127)Prepared according to General Scheme 1. ¹H-NMR (CD₃OD):. δ 7.20-711 (m,2H), 6.95 (m, 1H), 4.54 (d, 2H, J = 1.4). LC/MS: t_(R) = 4.8 min. MS(API-ES) m/z 220 (M + H⁺)

2-(4-Fluoro-3,5-dimethyl-phenoxy)-N-hydroxy-acetamide (Compound 168115)Prepared according to General Scheme 1. ¹H-NMR (CD₃OD):. δ 6.65 (d, 2H,J = 5.5), 4.47 (s, 2H), 2.21 (d, 6H, J = 2.0). LC/MS: t_(R) = 5.4 min.MS (API-ES) m/z 214 (M + H⁺)

TABLE 4 Compounds

(R,Z)-6-(benzyloxy)-2-(3-chloro-4-fluorophenoxy)-N-hydroxyhex-4- enamide(Compound 168160) Prepared according to General Scheme 6. LC/MS: t_(R) =8.1 min. MS (API-ES) m/z 380 (M + H⁺)

R)-6-(benzyloxy)-2-(3-chloro-4-fluorophenoxy)-N-hydroxyhexanamide(Compound 168187) Prepared according to General Scheme 6 ¹H-NMR (CD₃OD):δ 7.31 (m, 5H), 7.14 (t, 2H, J = 9.0), 7.07 (m, 1H), 6.90 (m, 1H), 4.54(t, 1H, J = 5.8), 4.48 (s, 2H), 3.50 (t, 2H, J = 5.7), 1.92 (m, 2H),1.70-1.51 (m, 4H). LC/MS: t_(R) = 1.07 min. MS (API-ES) m/z 382 (M + H⁺)

What is claimed is:
 1. A compound of the formula

where X is O, S, SO or SO₂; R¹ is F, Cl, Br, I, alkyl of 1-3 carbons,alkoxy of 1-3 carbons, thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN,CF₃, OCF₃, OH, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, COOH orCOO(C₁-C₆alkyl); m is an integer having the value of 1 to 3; R² is alkylof 1-6 carbons; C₁-C₆ alkylphenyl where phenyl is substituted with 0-3R¹ groups, C₂-C₆alkenylO(CH₂)_(n)phenyl where alkenyl has 2 to 6 carbonsand one double bond and phenyl is substituted with 0-3 R¹ groups, C₁-C₆alkylcyclohexyl, CH₂)_(n)OR³, (CH₂)_(n)NHR⁴, NR⁴C₁-C₆alkyl, (CH₂), CF₃,CH₂OCH₂-phenyl; (CH₂)_(n)NH(CH₂)_(n)R⁴, (CH₂)_(n)NR⁶R⁴,(CH₂)_(n)NR⁶(CH₂)_(n)R⁴, (CH₂)_(n)O(CH₂)_(n)R⁴, (CH₂)_(n)OR⁴, n is aninteger having the value of 1 to 8; R³ is H, alkyl of 1 to 6 carbons,alkylphenyl where the alkylgroup has 1 to 6 carbons and the phenyl issubstituted with 0-3 R¹ groups; R⁴ is H, cyclohexyl, C(O)alkyl of 1 to 4carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbons and thephenyl is substituted with 0-3 R¹ groups or with a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S, and N, orwith a 5 to 6 membered heteroaryl group having 1 to 2 heteroatomsselected from O, S and N and condensed with a phenylgroup, saidheteroaryl or condensed heteroaryl group itself substituted with 0-3 R¹groups, or R⁴ is C(O)(CH₂)_(p)COOH, (CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups or with a NO₂ group, or R⁴ isC(O)OC₁-C₆alkyl, or R⁴ is CH(CH₃)phenyl where the phenyl is substitutedwith 0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups, or R⁴ is C(O)CH(Ph)₂,C(O)—CH₂-(3PhO-)Ph, or R⁴ is a 5 to 6 membered heteroaryl group having 1to 2 heteroatoms selected from O, S, and N, or a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S and N andcondensed with a phenylgroup, said heteroaryl or condensed heteroarylgroup itself substituted with 0-3 R¹ groups, or R⁴ is CH₂heteroarylwhere the heteroaryl group is 5 or 6 membered and has 1 to 2 heteroatomsselected from O, S, or R⁴ is SO₂-alkyl of 1 to 6 carbons, SO₂-Ph wherethe phenyl is substituted with 0-3 R¹ groups or with NO₂ or with COOR⁵group, or R⁴ is C(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkylgroup has 1 to 4 carbons and where the phenyl is substituted with 0-3 R¹groups; p is an integer having the value of 0 to 4; R⁵ is alkyl of 1 to6 carbons or phenyl substituted with 0-3 R¹ groups or with an OPh group;R⁶ is alkyl of 1 to 6 carbons; the asterisk indicates an asymmetriccarbon, the wavy line represents a bond that can be in the R or in the Sconfiguration, or a pharmaceutically acceptable salt of said compound,with the proviso that compounds selected from the group consisting ofcompounds identified below with structural formulas and designations ofthe variables R¹

where R¹ is H, 2-Me, 4-Me, 4-Br, 2-phenyl, 2-(3-propenyl), 4-O-n-Bu,2-Me-4-Br, 2,4-diCl, 2,4-diBr, 2,5-diCl, 2,4,5-triCl, 2,5-diCl-4-Me, or2,4-diCl-4-Br, and

where R¹ is 2-phenyl, 2-(3-propenyl), 2,3-dimethyl, or 2,4-diCl, and

where R¹ is H, 2-Me, 2—Cl, 2-OMe, 3-Me, 3—Cl, 3-OMe, 3-CF₃, 4-OMe,4-SMe, or 4-phenyl, and

are not included in the claim.
 2. A compound in accordance with claim 1where X is O.
 3. A compound in accordance with claim 1 where X is S. 4.A compound in accordance with claim 1 where X is SO.
 5. A compound inaccordance with claim 1 where X is SO₂.
 6. A compound in accordance withclaim 1 where R¹ is selected independently from the group consisting ofF, Cl, methyl and methoxy.
 7. A compound in accordance with claim 6where m is an integer having the value of 2 or
 3. 8. A compound inaccordance with claim 7 where m is 2, one R¹ group is methyl in the 3(meta) position on the phenyl ring, and the other R¹ group is fluoro inthe 4 (para) position of the phenyl ring.
 9. A compound of the formula

where X is O, S, SO or SO₂; R² is H, alkyl of 1 to 6 carbons, (CH₂)₂OH,or (CH₂)₄OH; the asterisk represents that the adjacent carbon isasymmetric and the wavy line represents a bond which can be of either Ror S configuration, or a pharmaceutically acceptable salt of saidcompound.
 10. A compound in accordance with claim 9 where X is O.
 11. Acompound in accordance with claim 9 where X is S.
 12. A compound inaccordance with claim 9 where X is SO.
 13. A compound in accordance withclaim 9 where X is SO₂.
 14. A compound of the formula

where R¹ is H, or alkyl of 1 to 6 carbons; R² is (CH₂)_(n)NHR⁴, CH₂)OR⁴,CH₂)_(n)N(CH₃)R⁴, C₂₋₆alkenylOCH₂phenyl where alkenyl has one doublebond and the phenyl group is substituted with 0 to 3 groups selectedfrom methyl and fluoro; n is an integer selected from 1 to 6; R⁴ is(CH₂)_(p)phenyl, (CH₂)_(p)thienyl, (CH₂)_(p)furyl where the phenyl,thienyl and furyl groups are substituted with 0 to 3 groups selectedfrom methyl and fluoro; p is an integer selected from 1 to 3; theasterisk represents that the adjacent carbon is asymmetric and the wavyline represents a bond which can be of either R or S configuration, or apharmaceutically acceptable salt of said compound.
 15. A compound inaccordance with claim 14 where p is one (1).
 16. A compound inaccordance with claim 14 where R² is (CH₂)_(n)NHR⁴.
 17. A compound inaccordance with claim 14 where R² is CH₂)_(n)OR⁴.
 18. A compound inaccordance with claim 14 where R² is CH₂)_(n)N(CH₃)R⁴.
 19. A compound inaccordance with claim 14 where R² is C₂₋₆alkenylOCH₂phenyl.
 20. Acompound in accordance with claim 14 where R¹ is H.
 21. A compoundselected from the group consisting of structural formulas shown below

or a pharmaceutically acceptable salt of said compound.
 22. A compoundof the formula

or a pharmaceutically acceptable salt of said compound.
 23. A compoundof the formula

or a pharmaceutically acceptable salt of said compound.
 24. Apharmaceutical composition for the treatment of infection by bacillusanthraci in a mammal, including a human, adapted for systemicadministration containing a pharmaceutically acceptable excipient andone or more compounds having the formula below

where X is O, S, SO or SO₂; R¹ is F, Cl, Br, I, alkyl of 1-3 carbons,alkoxy of 1-3 carbons, thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN,CF₃, OCF₃, OH, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, COOH orCOO(C₁-C₆alkyl); m is an integer having the value of 1 to 3; R² is alkylof 1-6 carbons; C₁-C₆ alkylphenyl where phenyl is substituted with 0-3R¹ groups, C₂-C₆alkenylO(CH₂)_(n)phenyl where alkenyl has 2 to 6 carbonsand one double bond and phenyl is substituted with 0-3 R¹ groups, C₁-C₆alkylcyclohexyl, CH₂)_(n) OR³, (CH₂)_(n)NHR⁴, NR⁴C₁-C₆alkyl,(CH₂)_(n)CF₃, CH₂OCH₂phenyl; (CH₂)_(n)NH(CH₂)_(n)R⁴, (CH₂)_(n)NR⁶NR⁴,(CH₂)_(n)NR⁶(CH₂)_(n)R⁴, (CH₂)_(n)O(CH₂)_(n)R⁴, (CH₂)_(n)OR⁴, n is aninteger having the value of 1 to 8; R³ is H, alkyl of 1 to 6 carbons,alkylphenyl where the alkylgroup has 1 to 6 carbons and the phenyl issubstituted with 0-3 R¹ groups; R⁴ is H, cyclohexyl, C(O)alkyl of 1 to 4carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbons and thephenyl is substituted with 0-3 R¹ groups or with a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S, and N, orwith a 5 to 6 membered heteroaryl group having 1 to 2 heteroatomsselected from O, S and N and condensed with a phenylgroup, saidheteroaryl or condensed heteroaryl group itself substituted with 0-3 R¹groups, or R⁴ is C(O)(CH₂)_(p)COOH, (CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups or with a NO₂ group, or R⁴ isC(O)OC₁-C₆alkyl, or R⁴ is CH(CH₃)phenyl where the phenyl is substitutedwith 0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups, or R⁴ is C(O)CH(Ph)₂,C(O)—CH₂-(3PhO-)Ph, or R⁴ is a 5 to 6 membered heteroaryl group having 1to 2 heteroatoms selected from O, S, and N, or a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S and N andcondensed with a phenylgroup, said heteroaryl or condensed heteroarylgroup itself substituted with 0-3 R¹ groups, or R⁴ is CH₂heteroarylwhere the heteroaryl group is 5 or 6 membered and has 1 to 2 heteroatomsselected from O, S, or R⁴ is SO₂-alkyl of 1 to 6 carbons, SO₂-Ph wherethe phenyl is substituted with 0-3 R¹ groups or with NO₂ or with COOR⁵group, or R⁴ is C(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkylgroup has 1 to 4 carbons and where the phenyl is substituted with 0-3 R¹groups; p is an integer having the value of 0 to 4; R⁵ is alkyl of 1 to6 carbons or phenyl substituted with 0-3 R¹ groups or with an OPh group;R⁶ is alkyl of 1 to 6 carbons; the asterisk indicates an asymmetriccarbon, the wavy line represents a bond that can be in the R or in the Sconfiguration, or a pharmaceutically acceptable salt of said compound.25. A method of treating infection of a mammal, including a human being,by bacillus anthraci by administering to said mammal a pharmaceuticalcomposition containing a pharmaceutically acceptable excipient and oneor more compounds defined by formula in accordance with claim
 24. 26. Amethod of inhibiting the lethal factor enzyme released by bacillusanthraci where such inhibition is needed, said method comprisingcontacting said enzyme with one or more compounds defined by formula inaccordance with claim
 24. 27. A method in accordance with claim 26 wheresaid contacting comprises administering to a human being infected bybacillus anthraci a pharmaceutical composition containing apharmaceutically acceptable excipient and one or more compounds definedby formula in accordance with claims 24.